1. Managing the late consequences of CHD: What is the evidence for lipid management Prof Philip Barter The Heart Research Institute Sydney, Australia Slides prepared and presented by

2. Serum Cholesterol and CHD in 361,662 US Men: MRFIT 6-Year CHD Death Rate per 1000 Men Serum Cholesterol (mg/dl) 0 2 4 6 8 10 12 14 16 18140160180200220240260280300

3. Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants LDL HDL Pro-atherogenicAnti-atherogenic

4. Adhesion Molecule Molecule Monocyte Intima Vessel Lumen Endothelium LDL LDL MCP-1 Macrophage Cytokines Foam Cell MODIFIED LDL ROLE OF LDL IN CAUSING ATHEROSCLEROSIS

5. 0 10 20 30 CARE-Pra LIPID-Pra 4S-Sim CARE-Plac LIPID-Plac 4S-Plac Statin Trials: LDL-C Levels vs Events Secondary Prevention 21090 110 130150170 190 LDL-C (mg/dL) % with CHD event 70 TNT-Ator10 TNT-Ator80 HPS-Plac HPS-Sim IDEAL-Sim IDEAL-Ator

6. Median LDL-C (mg/dL) 20 40 60 80 100 120 Rand 30 days 4 months 8 months 16 months Final Pravastatin 40 mg (Median LDL-C 95 mg/dL) Atorvastatin 80 mg (Median LDL-C 62 mg/dL) 49%  21%  P<0.001 Cannon CP, et al. N Engl J Med. 2004;350:1495-504 PROVE-IT: Changes From Baseline LDL-C

7. PROVE-IT: All-cause Mortality or Major CV Events in All Randomized Subjects031821242730691215 Months of follow-up Pravastatin 40 mg (26.3%) Atorvastatin 80 mg (22.4%) 16% RRR P=0.005 30 25 20 15 10 5 0 % patients with event Cannon CP, et al. N Engl J Med. 2004;350:1495-504

8. Patient population: CHD CHD LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) Triglycerides  600 mg/dL (  6.8 mmol/L) Triglycerides  600 mg/dL (  6.8 mmol/L) Primary efficacy outcome measure: Time to occurrence of a major CV event: Time to occurrence of a major CV event: –CHD death –Nonfatal, non-procedure-related MI –Resuscitated cardiac arrest –Fatal or nonfatal stroke Atorvastatin 10 mg Open-label run-in n=15,464 8 weeks 1-8 weeks Screening and wash-out n=18,469 Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) Median follow-up = 4.9 years Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) Double-blind period n=10,001 LDL-C <130 mg/dL (<3.4 mmol/L) n=4995 n=5006 Baseline TNT-Study Design

9. FinalScreen031224364860 P<0.001 Baseline 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Mean LDL-C (mmol/L) Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) 0 20 40 60 80 100 120 140 160 Study visit (months) Mean LDL-C (mg/dL) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Changes in LDL-C By Treatment Group

10. HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 Proportion of patients experiencing major cardiovascular event 0 0.05 0.10 0.15 Atorvastatin 10 mg Atorvastatin 80 mg 0123456 Time (years) Relative risk reduction = 22% LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Primary Efficacy Outcome Measure: Major Cardiovascular Events

11. Proportion of patients experiencing fatal or nonfatal stroke 0 0.01 0.02 0.04 0.03 HR = 0.75 (95%CI 0.59, 0.96) P=0.02 Relative risk reduction = 25% Atorvastatin 10 mg Atorvastatin 80 mg 0123456 Time (years) LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Stroke (Fatal or nonfatal)

12. TNT-Primary Endpoint P-value 117 (2.3) 25 (0.5) 243 (4.9) 101 (2.0) 434 (8.7) Atorvastatin 80 mg 155 (3.1) 26 (0.5) 308 (6.2) 127 (2.5) 548 (10.9) Atorvastatin 10 mg No. of patients (%) 0.0040.78 Nonfatal MI 0.020.75Stroke 0.890.96 Resuscitated cardiac arrest 0.090.80 CHD death End point 0.78 HR 0.0002 Major CV event LaRosa JC, et al. N Eng J Med. 2005;352

13. TNT-Safety 2 (0.04)3 (0.06)Rhabdomyolysis* 60 (1.2)9 (0.2)AST/ALT elevation >3  ULN 406 (8.1) 241 (4.8) 289 (5.8) 234 (4.7) Treatment-related AEs Treatment-related myalgia No. of patients (%) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) *No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria 2 for rhabdomyolysis 2. Pasternak RC et al. Circulation. 2002;106:1024-1028 1. LaRosa JC, et al. N Eng J Med. 2005;352

14. TNT-Major CVE by on-treatment LDL Quintiles 0 2 4 6 8 10 12 14 16 Major CVE (%) < 1.6 1.82.22.5 > 2.7 LDL-C quintile (mmol/L)

15. TNT-Major CVE by on-treatment LDL Quintiles 0 2 4 6 8 10 12 14 16 Major CVE (%) < 1.6 1.82.22.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

16. 0 1 2 3 4 5 6 7 8 All-cause mortality (%) TNT-All-cause mortality by on-treatment LDL Quintiles < 1.6 1.82.22.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

17. 0 1 2 3 4 Non-CV deaths (%) TNT-Non-CV mortality by on-treatment LDL Quintiles < 1.6 1.82.22.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

18. 0 2 4 6 8 10 12 14 16 4S (S40) 4S (P) CARE (P40) CARE (P) LIPID (P40) LIPID (P) HPS (S40) HPS (P) Mortality (%) TNT (A10) TNT (A80) Cardiovascular Mortality in Secondary Prevention Studies

19. 0 2 4 6 8 10 12 14 16 Mortality (%) 4S(S40)4S(P)CARE (P40) CARE (P) LIPID (P40) LIPID(P)HPS (S40) HPS(P)TNT (A10) TNT (A80) Non-cardiovascular Mortality in Secondary Prevention Studies

20. Diabetic Subgroup in TNT Atorva 10 mg N=753 Atorva 80mg N=748 CHD death31 (4.1 %)23 (3.1%) Nonfatal non PR MI61 (8.1%)49 (6.6%) Resuscitated Cardiac Arrest0 (0.0%)3 (0.4%) Stroke43 (5.7%)28 (3.7%) Total135 (17.9%)103 (13.8%) Log-rank p HR (95% CI) 0.0263 0.75 (0.58, 0.97) Shepherd et al, Diabetes Care 2006;29:1220.

21. Metabolic Syndrome Subgroup in TNT Atorva 10 mg N=1771 Atorva 80mg N=1706 CHD death47 (2.7%)32 (1.9%) Nonfatal non PR MI145 (8.2%)98 (5.7%) Resuscitated Cardiac Arrest 3 (0.2%)6 (0.4%) Total195 (11%)136 (8%) Log-rank p HR (95% CI) 0.0026 0.72 (0.57, 0.89) Deedwania et al. Lancet 2006

22. 4.8-year follow-up 8888 patients Patient population  Enrolled at 190 sites throughout Scandinavia and the Netherlands  Diagnosed with CHD  Previous hospitalization with MI, and eligible for statin therapy Open-label period with blinded end point evaluations Atorvastatin 80 mg/day Simvastatin 20 mg/day (titrated to 40 mg if required) IDEAL - Protocol Pedersen et al. Am J Cardiol. 2004;94:720-721; Pedersen et al. JAMA. 2005;294:2437-2445. Secondary  Cardiovascular/coronary events  Cerebrovascular events  PAD  Hospitalization with primary diagnosis of CHF  All-cause mortality Primary  Time to occurrence of a major coronary event −CHD death −Nonfatal MI −Resuscitated cardiac arrest

23. Mean LDL-C = 104 mg/dL (2.7 mmol/L) Pedersen et al. JAMA. 2005;294:2437-2445. 0 70 80 90 100 110 120130Baseline Week 12 Year 1 Year 2 Year 3 Year 4 Year 5 LDL-C (mg/dL) Atorvastatin Simvastatin 0 1.8 2.0 2.3 2.6 2.8 3.1 3.4 LDL-C (mmol/L) Mean LDL-C = 81 mg/dL (2.1 mmol/L) IDEAL: Effect of Treatment On LDL-C

24. IDEAL: Composite End Points Cumulative Hazard (%) 0 4 8 1216Simvastatin Atorvastatin HR=0.89, P=.07 Cumulative Hazard (%) HR=0.87, P=.02 Years Since Randomization Cumulative Hazard (%) 012345 0 10 20 3040 HR=0.84, P<.001 Cumulative Hazard (%) HR=0.84, P<.001 Any CHD Major Coronary Event Any Cardiovascular Disease Major Cardiovascular Disease Years Since Randomization 012345 0 10 20 3040 012345 012345 0 4 8 1216 Pedersen et al. JAMA. 2005;294:2437-2445.

25. MIRACL Study Design 4 months 3073 patients Atorvastatin 80 mg Non-Q-wave infarction or unstable angina Non-Q-wave infarction or unstable angina Randomised 24–96 hours from admission Randomised 24–96 hours from admission Exclusions: Exclusions: Planned CABG/PTCA Planned CABG/PTCA Prior Q-wave <28 days Prior Q-wave <28 days CABG <3 months, PTCA <6 months CABG <3 months, PTCA <6 months IIIb/IV CHF IIIb/IV CHF TC >3.1 mmol/L (270mg/dL) TC >3.1 mmol/L (270mg/dL) Patient population Primary end point: Time to ischaemic events (CHD death, non- fatal MI, cardiac arrest, documented angina requiring hospitalisation) Time to ischaemic events (CHD death, non- fatal MI, cardiac arrest, documented angina requiring hospitalisation) Usual care + double-blind placebo Schwartz et al; JAMA. 2001;285:1711-1718.

26. MIRACL Results Effects on LDL-C: Placebo group124 mg/dl Atorvastatin group 74 mg/dl Schwartz et al; JAMA. 2001;285:1711-1718.

27. MIRACL Results Effects on primary endpoint (death, non-fatal MI, cardiac arrest, recurrent ischemia requiring hospitalisation) Placebo group17.4% Atorvastatin group 14.8% 16% reduction (p< 0.05) Schwartz et al; JAMA. 2001;285:1711-1718.

28. MIRACL Results Effects on stroke (secondary endpoint) Placebo group24 Atorvastatin group 12 (p< 0.05) Schwartz et al; JAMA. 2001;285:1711-1718.

29. MIRACL Conclusion MIRACL provides convincing evidence of the benefits of commencing aggressive LDL lowering very early in patients with acute coronary syndromes Schwartz et al; JAMA. 2001;285:1711-1718.

30. ARMYDA trial: Study design 153 patients Stable Angina Positive stress test Indication to PCI No previous statin treatmentAtorvastatin 40 mg/day N=76 PlaceboN=77 PCI Randomization ClinicalFollow-up 7 days 1° Blood sample before PCI 2°-3° Blood samples 8 and 24 h post-PCI 30 days CK MB, Tn-I, Myoglobin CK MB, Tn-I, Myoglobin Pasceri et al, 2004; Circulation 110:674-678

31. Primary end point Primary end point Incidence of MI, defined as post-PCI increase of CK-MB > 2 times UNL Pasceri et al, 2004; Circulation 110:674-678

32. Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL) P=0.025 ARMYDA trial: Primary end point 0 5 10 15 20 AtorvastatinPlacebo CK-MB (%) 18 5 Pasceri et al, 2004; Circulation 110:674-678

33.  The ARMYDA randomized trial demonstrates that a short pretreatment with atorvastatin decreases the incidence of myocardial injury during coronary intervention compared with placebo, thereby improving clinical outcome  These results have the potential to influence practice patterns concerning pharmacological therapy prior to percutaneous coronary revascularization ARMYDA trial: Conclusions Pasceri et al, 2004; Circulation 110:674-678

34. End point Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Any major vascular event 1097313350 0.78 (0.76-0.80) Any major coronary event 51056512 0.75 (0.70-0.82) Any stroke 23022680 0.82 (0.74-0.92) All statin clinical outcome trials Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) CTT Collaborators. Lancet. 2010; 376:1670-1681. Number of Events Any coronary revascularisation5353 6807 6807 0.71 (0.65-0.78)

35. Any stroke 572 663 663 0.74 (0.59-0.92) End point Aggressive(n=19829) Moderate (n=19783) Relative risk (95% CI) Any major vascular event 38374416 0.72 (0.66-0.78) Any major coronary event 17251973 0.74 (0.65-0.85) Effects of aggressive vs moderate therapy with statins Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Number of Events Any coronary revascularisation2250 2741 2741 0.66 (0.60-0.73) CTT Collaborators. Lancet. 2010; 376:1670-1681.

36. SubgroupTreatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Type 1 diabetes 145192 0.77 (0.58-1.01) Type 2 diabetes 24942920 0.80 (0.74-0.86) All statin clinical outcome trials: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events No diabetes 827210163 0.78 (0.75-0.81) CTT Collaborators. Lancet. 2010; 376:1670-1681.

37. Relative risk (95% CI) Type 1 diabetes 88 0.74 (0.02-22.21) Type 2 diabetes 703792 0.76 (0.59-0.98) Number of Events No diabetes 31263616 0.71 (0.63-0.80) Aggressive vs moderate statin therapy: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Aggressive(n=19829) Moderate (n=19783) Subgroup CTT Collaborators. Lancet. 2010; 376:1670-1681.

38. Baseline LDL-C Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L 9101012 0.78 (0.61-0.99) 2 - 2.5 mmol/L 15281729 0.77 (0.67-0.89) All statin clinical outcome trials: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events 2.5 - 3.0 mmol/L 18662225 0.77 (0.70-0.85) 3 - 3.5 mmol/L 20072454 0.76 (0.70-0.82) > 3.5 mmol/L 45085736 0.80 (0.76-0.83) Heterogeneity trend test: p=0.3 CTT Collaborators. Lancet. 2010; 376:1670-1681.

39. Baseline LDL-C Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L 704795 0.71 (0.52-0.98) 2 - 2.5 mmol/L 11891317 0.77 (0.64-0.94) Aggressive vs moderate therapy: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Number of Events 2.5 - 3.0 mmol/L 10651203 0.81 (0.67-0.97) 3 - 3.5 mmol/L 517633 0.61 (0.46-0.81) > 3.5 mmol/L 303398 0.64 (0.47-0.86) Heterogeneity trend test: p=0.2 CTT Collaborators. Lancet. 2010; 376:1670-1681.

40. Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Male871210725 0.77 (0.74-0.80) Female24942920 0.80 (0.74-0.86) All statin clinical outcome trials: effects of gender Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Subgroup Heterogeneity trend test: p=0.04 CTT Collaborators. Lancet. 2010; 376:1670-1681.

41. Duration (years) Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Year 0-1 34973952 0.88 (0.84-0.93) Year 1-2 21122645 0.77 (0.73-0.82) All clinical outcome trials: effects of duration of treatment Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Year 2-3 17632318 0.73 (0.69-0.78) Year 3-4 15081954 0.72 (0.68-0.77) Year 4-5 12241486 0.77 (0.72-0.83) Year 5+ 869995 0.76 (0.69-0.85) CTT Collaborators. Lancet. 2010; 376:1670-1681.

42. Effects of other subgroups on the ability of statins to reduce major vascular events No effect of: Prior vascular disease Prior vascular disease Age Age Blood pressure Blood pressure BMI BMI Smoking Smoking Estimated GFR Estimated GFR CTT Collaborators. Lancet. 2010; 376:1670-1681.

43. Comparison Treatment-armControl-arm Relative risk (95% CI) More vs less statin 5 trials (n=39,612) 14661472 1.02 (0.89-1.18) Statin vs Control 21 Trials (n=129,526 35943592 1.00 (0.95-1.04) All statin clinical outcome trials: effects on Cancer Relative risk of cancer per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol Cancer incidence All 26 trials (n=169,138)50605064 1.00 (0.96-1.04) CTT Collaborators. Lancet. 2010; 376:1670-1681.